1. Field of the Invention
This invention relates to 7-(2,3-dihydroxypropyl)-1,3-di-n-propylxanthine, its use as a bronchodilator, i.e., a bronchial muscle relaxant and to pharmaceutical compositions containing it.
2. Description of the Prior Art
Theophylline (1,3-dimethylxanthine)represented by the following structure ##STR1## is a naturally occurring xanthine alkaloid which was first reported as a therapeutic agent in asthma nearly 55 years ago. Its use as an oral bronchodilator did not become popular until the late 1930's. It was soon learned, however, that although theophylline was effective, its lack of water solubility and ability to produce undesirable side effects detracted from its usefulness. Consequently, continual effort was directed toward improving the water solubility of theophylline as well as toward synthesizing various derivatives in an attempt to increase safety while retaining the desirable pharmacological characteristics.
Solubilization of theophylline has been achieved by forming addition compounds like theophylline ethylenediamine (aminophylline), salts such as choline theophyllinate (oxtriphylline), or combinations with sodium acetate or sodium glycinate. Unfortunately, these "soluble" theophylline preparations have not served to appreciably reduce the incidence of undesirable effects on the gastrointestinal, cardiovascular, renal, and central nervous systems.
Attempts to modify the chemical structure of theophylline to obtain a compound with greater bronchodilator selectively has not met with measurable success. Compounds with increased bronchodilator potency have been made but at the expense of decreased tolerance. The only synthetic derivative of theophylline that has gained any degree of therapeutic acceptance is dyphylline, 7-(2,3-dihydroxypropyl) 1,3-dimethylxanthine represented by the following formula. ##STR2## Dyphylline possesses inherent high water solubility and few of the usual theophylline-like side effects; however, it also possesses less bronchodilator potency than theophylline.
It is apparent from the effects of dyphylline that 1,3-dihydroxypropyl substitution at position 7 of the basic theophylline molecule markedly decreases overall potency, in regard to both therapeutic and side effects. Roth et al. (J. Pharmacol, Exp. Ther. 121:487, 1957) observed this same phenomenon with 7-.beta.-hydroxypropyl-1,3-dimethylxanthine as did Armitage et al. (Brit. J. Pharmacol. 17:196, 1961) with a series of 7-hydroxyalkyl-6-thioxanthines. From the reports of Roth et al. and McColl et al. (J. Pharmacol. Exp. Ther. 116:343, 1956), it is shown that 7-dihydroxypropyl substitution decreases activity more than 7-monohydroxypropyl substitution.
On the other hand, various investigators have found that the pharmacologic activity of theophylline can be increased by dialkyl substitution at positions 1 and 3. Kattus et al. (Bull. John Hopkins Hosp. 89:1-8, 1951) demonstrated that 1,3-diethyl, 1,3-dipropyl, and 1,3-dibutyl xanthine exhibited extremely potent diuretic and emetic properties. Unfortunately, bronchodilator action was not assessed. Armitage et al. evaluated an entire series of 1,3-dialkyl substituted 6-thioxanthines. Most of the compounds tested, including the 1,3-dipropyl derivative, possessed potent bronchodilator activity and were potent emetic agents.
It would appear, therefore, from these literature reports that neither 7-hydroxyalkyl nor 1,3-dialkyl substitution of theophylline alone serves to better the therapeutic efficacy of the molecule as a bronchodilator. The former decreases side-effects at the expense of potency and the latter increases potency at the expense of tolerance.
U.S. Pat. No. 2,756,229 discloses a series of substituted theophyllines having both 7-monohydroxyalkyl and 1,3-dialkyl substituents. Specially disclosed are those compounds represented by Formulae III and IV. ##STR3## The are claimed by the patentee to be strong diuretics in comparison with theophylline and at the same time are said to be well tolerated. Nothing is disclosed about their bronchodilator properties.
Applicant has found that although Compounds III and IV are more potent bronchodilators than theophylline they are therapeutically undesirable because of increased undesirable emetic, cardiovascular and central nervous system (CNS) effects.
Accordingly, a compound comparable to theophylline as a bronchodilator, but having reduced adverse side effects and increased water solubility would be an advancement in the art.